US3883546A - S-heterocyclic derivatives of phosphine or phosphite gold mercaptides - Google Patents

S-heterocyclic derivatives of phosphine or phosphite gold mercaptides Download PDF

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Publication number
US3883546A
US3883546A US384666A US38466673A US3883546A US 3883546 A US3883546 A US 3883546A US 384666 A US384666 A US 384666A US 38466673 A US38466673 A US 38466673A US 3883546 A US3883546 A US 3883546A
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United States
Prior art keywords
gold
triethylphosphine
chloro
mol
phosphine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US384666A
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English (en)
Inventor
Blaine M Sutton
Joseph Weinstock
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SmithKline Beecham Corp
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SmithKline Corp
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Filing date
Publication date
Application filed by SmithKline Corp filed Critical SmithKline Corp
Priority to US384666A priority Critical patent/US3883546A/en
Priority to ZA00744598A priority patent/ZA744598B/xx
Priority to JP49085967A priority patent/JPS5761035B2/ja
Priority to BE147055A priority patent/BE818218A/xx
Priority to SE7409800A priority patent/SE7409800L/xx
Priority to AU71807/74A priority patent/AU480489B2/en
Priority to CA206060A priority patent/CA1054609A/en
Priority to GB3376374A priority patent/GB1422899A/en
Priority to FR7426773A priority patent/FR2240014B1/fr
Priority to DE2437147A priority patent/DE2437147C2/de
Priority to US05/542,976 priority patent/US3947565A/en
Application granted granted Critical
Publication of US3883546A publication Critical patent/US3883546A/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • This invention relates to novel S-heterocyclic derivatives of phosphine or phosphite gold mercaptides which have useful pharmacological activity. More specifically, the compounds of this invention have antiarthritic activity as measured by their ability to inhibit adjuvant-induced polyarthritis in rats.
  • R is lower alkyl, lower alkoxy, phenyl or phenoxy, with each alkyl or alkoxy having from one to three carbon atoms;
  • X is S, NH, NCH or O
  • R and R are hydrogen or together form a 1,2-benzo radical
  • Preferred compounds of this invention are represented by Formula I where R is lower alkyl. Also preferred are those compounds of Formula I where the heterocyclic moiety is 2-thiaz olinyl, 2-benzimidazolyl and 2-benzoxazolyl.
  • the compounds of this invention are prepared by reaction of an heterocyclic mercaptan compound with an appropriate phosphine or phosphite gold(l) halide, preferably chloride, in the presence of alkali such assodium hydroxide in a solvent such as aqueous alcoholchloroform at about 25 for approximately 1 hour in a nitrogen atmosphere.
  • an appropriate phosphine or phosphite gold(l) halide preferably chloride
  • the phosphine or phosphite gold halides employed as starting materials are prepared by reaction of a cold (10 to 5) solution of gold(l) chloride, prepared by mixing thiodiglycol and gold acid chloride trihydrate in aqueous alcohol, with an appropriate phosphine or.
  • phosphite such as triethylphosphine.
  • Other procedures which may be applied to the preparation of these intermediates are found in J. Chem. Soc. 1828 (1937) and 1235 (1940) and Australian J. Chem. 19:547 (1966).
  • the anti-arthritic activity of the compounds of this invention is measured by their ability to inhibit adjuvant-induced polyarthritis in rats.
  • the compounds of Formula I produce marked inhibition of the development of adjuvant arthritis in rats at daily oral doses as low as about 20 mg. per kilogram of body weight. Of particular importance isthe attainment of significant serum levels of gold following oral administration of these doses.
  • Adjuvant arthritis in rats is produced by a single injection of 0.75 mg. of Mycobacterium butyricum suspended in white paraffin (NF) into a hindpaw (left footpad).
  • the injected leg becomes inflamed and reaches a maximum volume in 3 to 5 days (primary lesion).
  • the animals exhibit a decrease in body weight gain during this initial period.
  • Adjuvant arthritis (secondary phase) occurs after a delay of approximately 10 days and is characterized by inflammation of the noninjected sites (right hind leg), decrease in body weight gain and further increases in the volume of the injected hind leg.
  • the compounds of Formula I administered in the doses described above beginning on the day of ad- 5 juvant injection and continuing for 17 days thereafter,
  • the compounds of this invention are administered in conventional dosage unit forms by incorporating an amount sufficient to produce anti-arthritic activity, without toxic effects, with a nontoxic pharmaceutical carrier according to accepted procedures.
  • the dosage units will contain an S-heterocyclic derivative of a phosphine or phosphite gold mercaptide of Formula I in an amount of from about 0.5 mg. to about 25 mg., preferably 0.5 mg. to 10 mg. calculated on gold content, per unit.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil,
  • the carrier or dili uent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be employed.
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
  • a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • the method of producing anti-arthritic activity in ac-' cordance with this invention comprises administering internally to an animal organism an S-heterocyclic derivative of a phosphine or phosphite gold mercaptide of Formula I, usually combined with a pharmaceutical carrier, in an amount sufficient to produce antiarthritic activity without limiting side effects.
  • the active medicament will be administered in a dosage unit, as described above, orally or parenterally, the oral route being preferred.
  • Advantageously equal doses will be administered one or two times daily with the daily dosage regimen being from about 0.5 mg. to about 50 mg., preferably 0.5 mg. to about 20 mg., calculated on gold content.
  • the pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.
  • reaction mixture was stirred at 25 for l-hour under nitrogen, filtered and the filtrate was evaporated to dryness to give a residue which was dissolved in methanol and treated with activated charcoal to give the title compound as white crystals, m.p. l00l02 (methanol).
  • EXAMPLE 5 A mixture of 11.82 g. (0.03 mol.) of gold acid chloride trihydrate and 1.9 g. (0.065 mol.) of thiodiglycol in m1. of aqueous ethanol (3:2) was stirred until the color of auric gold disappeared. The almost colorless solution was cooled below 5 and an equally cold solution of 5.6 g. (0.035 mol.) of triisopropylphosphine in 20 ml. of ethanol was added dropwise. The volume of the final reaction mixture was increased to 250 ml. with 1:1 aqueous ethanol in order to maintain a fluid mixture. After addition the mixture was stirred in the cold for 45 minutes.
  • 2-benzoxazolylthio(triisopropylphosphine)gold is prepared by substitution of an equivalent amount of chloro(triisopropylphosphine)gold in the procedure of Example 3 for chloro(triethylphosphine)- gold.
  • 2-benzimidazolylthio(triphenylphosphine)-gold and 2 benzoxazolylthio(triphenylphosphine)gold are obtained by substitution of equivalent amounts of chloro(triphenylphosphine)gold in the procedures of Examples 2 and 3, respectively, for chloro(t riethylphosphine)gold.
  • 2-benzimidazolylthio(diethylphenylphosphine(gold and 2-benzoxazolylthio(diethylphenylphosphine)gold are obtained by substitution of equivalent amounts of chloro(diethylphenylphosphine)gold in the procedures of Examples 2 and 3, respectively, for ch ro(triethylphosphine)gold.
  • bromo(trialkylphosphine)- gold complexes are prepared, for example, br0mo(triethylphosphine)gold.
  • the mercapto heterocycles listed above may be allowed to react with the other phosphine or phosphite gold halides disclosed herein.
  • R is lower alkyl, lower alkoxy, phenyl or phenoxy, with each alkyl or alkoxy having from one to three carbon atoms;
  • R is lower alkyl.
  • a compound as claimed in claim 2 where the heterocyclic moiety is 2-thiazolinyl, 2-benzimidazolyl or 2-benzoxazolyl.
  • a compound as claimed in claim 3 being the compound Z-thiazolinylthio(triethylphosphine)gold.
  • a compound as claimed in claim 3 being the compound 2-benzimidazolylthio'(triethylphosphine)gold.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US384666A 1973-08-01 1973-08-01 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides Expired - Lifetime US3883546A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US384666A US3883546A (en) 1973-08-01 1973-08-01 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides
ZA00744598A ZA744598B (en) 1973-08-01 1974-07-18 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides
JP49085967A JPS5761035B2 (enExample) 1973-08-01 1974-07-26
BE147055A BE818218A (fr) 1973-08-01 1974-07-29 Nouveaux derives s-heterocycliques de phosphine-or ou phosphine-or mercaptides
AU71807/74A AU480489B2 (en) 1973-08-01 1974-07-30 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides
SE7409800A SE7409800L (enExample) 1973-08-01 1974-07-30
CA206060A CA1054609A (en) 1973-08-01 1974-07-31 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides
GB3376374A GB1422899A (en) 1973-08-01 1974-07-31 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides and anti-arthritic compositions comprising them
FR7426773A FR2240014B1 (enExample) 1973-08-01 1974-08-01
DE2437147A DE2437147C2 (de) 1973-08-01 1974-08-01 Phosphin- und Phosphit-Goldkomplexe und ihre Verwendung
US05/542,976 US3947565A (en) 1973-08-01 1975-01-22 Anti-arthritic compositions comprising s-heterocyclic derivatives of phosphine or phosphite gold mercaptides and methods of producing anti-arthritic activity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US384666A US3883546A (en) 1973-08-01 1973-08-01 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides

Related Child Applications (1)

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US05/542,976 Division US3947565A (en) 1973-08-01 1975-01-22 Anti-arthritic compositions comprising s-heterocyclic derivatives of phosphine or phosphite gold mercaptides and methods of producing anti-arthritic activity

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US3883546A true US3883546A (en) 1975-05-13

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US384666A Expired - Lifetime US3883546A (en) 1973-08-01 1973-08-01 S-heterocyclic derivatives of phosphine or phosphite gold mercaptides

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US (1) US3883546A (enExample)
JP (1) JPS5761035B2 (enExample)
BE (1) BE818218A (enExample)
CA (1) CA1054609A (enExample)
DE (1) DE2437147C2 (enExample)
FR (1) FR2240014B1 (enExample)
GB (1) GB1422899A (enExample)
SE (1) SE7409800L (enExample)
ZA (1) ZA744598B (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4165380A (en) * 1977-02-25 1979-08-21 Smithkline Corporation Bis(sulfide)gold(1+) salts
US4172833A (en) * 1978-03-20 1979-10-30 R. T. Vanderbilt Company, Inc. Process for preparation of 2-mercaptotoluimidazole and salts thereof
WO1985000747A1 (en) * 1983-08-10 1985-02-28 Stockel Richard F Use of selenium-containing compounds for negating the toxic effects of gold compounds used in the treatment of rheumatoid arthritis, and a novel selenium-containing gold compound and use thereof as an anti-rheumatoid arthritis medicine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3148554A1 (en) * 2014-05-28 2017-04-05 Auspherix Limited Gold (i)-phosphine compounds as anti-bacterial agents
CN106573944A (zh) * 2014-05-28 2017-04-19 奥斯弗伦里克斯有限公司 作为抗菌剂的金(i)‑膦化合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3502690A (en) * 1965-09-03 1970-03-24 Boehringer Sohn Ingelheim (bis - dimethylamino)-(3 - phenyl - 5 - amino-1,2,4-triazolo) - phosphineoxide triphenyl-chlorostannate
US3755329A (en) * 1970-12-22 1973-08-28 Du Pont Nitrogen-heterocyclylgold(i) compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3502690A (en) * 1965-09-03 1970-03-24 Boehringer Sohn Ingelheim (bis - dimethylamino)-(3 - phenyl - 5 - amino-1,2,4-triazolo) - phosphineoxide triphenyl-chlorostannate
US3755329A (en) * 1970-12-22 1973-08-28 Du Pont Nitrogen-heterocyclylgold(i) compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4165380A (en) * 1977-02-25 1979-08-21 Smithkline Corporation Bis(sulfide)gold(1+) salts
US4172833A (en) * 1978-03-20 1979-10-30 R. T. Vanderbilt Company, Inc. Process for preparation of 2-mercaptotoluimidazole and salts thereof
WO1985000747A1 (en) * 1983-08-10 1985-02-28 Stockel Richard F Use of selenium-containing compounds for negating the toxic effects of gold compounds used in the treatment of rheumatoid arthritis, and a novel selenium-containing gold compound and use thereof as an anti-rheumatoid arthritis medicine

Also Published As

Publication number Publication date
SE7409800L (enExample) 1975-02-03
AU7180774A (en) 1976-02-05
ZA744598B (en) 1975-07-30
CA1054609A (en) 1979-05-15
DE2437147C2 (de) 1983-03-03
GB1422899A (en) 1976-01-28
JPS5761035B2 (enExample) 1982-12-22
BE818218A (fr) 1975-01-29
FR2240014B1 (enExample) 1978-07-21
JPS5041859A (enExample) 1975-04-16
DE2437147A1 (de) 1975-02-13
FR2240014A1 (enExample) 1975-03-07

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